The long-term objective of this research is to provide a clearer understanding of the molecular basis of synaptic plasticity and how this relates to learning, memory, and behavior. This is an important health-related issue because abnormal neuronal function has been implicated in the pathoetiology of several diseases including psychiatric disorders, ischemic brain injury, and Alzheimer's disease. This line of research is also relevant to age-related changes in memory function. We propose to study the mechanisms through which an overexpressed Ca2+-independent form of calmodulin-dependent kinase II (CaMKII-Asp286) disrupts both synaptic plasticity in the hippocampus and behavioral performance on spatial memory-dependent tasks. Our specific aims are (1) to determine whether calmodulin trapping by CaMKII-Asp286 is sufficient to produce the physiological and behavioral phenotype observed in mice expressing this Ca2+-independent form of CaMKII, (2) to determine if disruption of synaptic plasticity by CaMKII-Asp286 in the CA1 region of the hippocampus alone is sufficient to produce a deficit in spatial learning and memory, and (3) to identify which stage of learning and memory, either acquisition, consolidation, or recall, is sensitive to disruption by expression of the CaMKII-Asp286 transgene. These aims will be accomplished by studying the activity of CaMKII-Asp286 in vitro, by creating two new lines of transgenic mice, and by testing these and existing transgenic animals on spatial tasks. First, we plan to create a line of mice carrying a Ca2+-independent form of CaMKII that has no kinase activity in order to determine if calmodulin trapping alone can create a phenotype similar to that seen in our existing mice. Using the CRE-lox system, we will create a second line of mice which expresses the CaMKII-Asp286 only in the CA1 region of the hippocampus. Finally, the existing mice we plan to study suppress CaMKII-Asp286 expression in response to tetracycline. This will allow us to regulate at which time after learning the transgene is expressed and is capable of disrupting spatial memory.